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ARTICLE

Stability of Trimethoprim in Admixtures of


Trimethoprim–Sulfamethoxazole Prepared
in Polyvinylchloride Bags and Glass Bottles
James M. Curtis and David J. Edwards

ABSTRACT RÉSUMÉ
Objective: To compare the stability of various concentrations of Objectif : Comparer la stabilité de diverses concentrations
trimethoprim in admixtures of trimethoprim–sulfamethoxazole de triméthoprime dans des mélanges triméthoprime–
prepared in polyvinylchloride (PVC) bags and glass bottles. sulfaméthoxazole préparés dans des sacs en polychlorure de
vinyle (PVC) et des bouteilles de verre.
Methods: Concentrated trimethoprim–sulfamethoxazole was
added to 250-mL evacuated glass containers and 100-mL PVC Méthodes : L’association triméthoprime–sulfaméthoxazole a été
bags containing 5% dextrose in water (D5W) or normal saline ajoutée à des flacons sous vide de 250 mL et des sacs en PVC de
(NS) to produce a final trimethoprim concentration of 1.08 or 1.60 100 mL contenant du dextrose à 5 % dans l’eau (D5W) ou une
mg/mL. Samples were stored at room temperature under ambient solution physiologique (NS), pour obtenir une concentration
light. Chemical stability was assessed at 12 and 24 h by a finale de triméthoprime de 1,08 ou 1,60 mg/mL. Les échantillons
stability-indicating high-performance liquid chromatography ont ensuite été entreposés à la température et à la lumière
assay. Physical stability was based on visual inspection of the ambiantes. La stabilité chimique a été évaluée à 12 et à 24 heures
samples at 12 and 24 h. Selected samples were filtered or à l’aide d’une épreuve de stabilité par chromatographie liquide à
examined microscopically to confirm the results of visual haute pression. La stabilité physique a été évaluée par l’inspection
inspection. The pH of all samples was measured at 0 and 24 h. visuelle des échantillons à 12 et à 24 heures. Des échantillons
choisis ont été filtrés et examinés au microscope pour confirmer
Results: The concentration of trimethoprim at 24 h averaged les résultats de l’inspection visuelle. Le pH de tous les échantillons
more than 95% of the starting concentration irrespective of a été mesuré à 0 et à 24 heures.
container, concentration, or IV solution. No visible precipitate was
Résultats : La moyenne des concentrations en triméthoprime à 24
observed in any admixture prepared in PVC bags. Admixtures
heures était de 95 % de la concentration initiale, indépendamment
prepared with D5W in glass bottles at a concentration of 1.08
du contenant, de la concentration ou de la solution IV. Aucun
mg/mL were clear at 12 h, but a precipitate was present in 5 of
précipité visible n’a été observé dans les mélanges préparés dans
the 20 samples at 24 h. Several samples prepared with NS in glass
des sacs en PVC. Les mélanges préparés dans des bouteilles de
at 1.60 mg/mL precipitated within 12 h, and 14 of the 20 had
verre avec du D5W, à des concentrations de 1,08 mg/mL, étaient
precipitated by 24 h.
clairs à 12 heures, mais 5 des 20 échantillons présentaient un
Conclusions: Admixtures containing trimethoprim exhibit précipité à 24 heures. Plusieurs échantillons préparés dans des
chemical and physical stability over a 24-h period when prepared bouteilles de verre avec du NS, à des concentrations de
in PVC bags. Physical stability in PVC bags is superior to that in 1,60 mg/mL, ont formé un précipité après 12 heures et 14 des
glass bottles, particularly at higher concentrations; use of PVC 20 échantillons ont formé un précipité après 24 heures.
bags would allow the shelf life of admixtures to be extended to Conclusions : Les mélanges contenant de la triméthoprime sont
24 h. D5W is the preferred IV solution for preparation of such chimiquement et physiquement stables sur une période de
admixtures. 24 heures, lorsqu’ils sont préparés dans des sacs en PVC. La
stabilité physique des mélanges est supérieure dans les sacs en
PVC que dans les bouteilles de verre, particulièrement à de fortes
Key words: trimethoprim, sulfamethoxazole, stability,
concentrations ; le recours à des sacs en PVC permettrait de
polyvinylchloride, glass
prolonger la durée de conservation des mélanges jusqu’à
24 heures. Le D5W constitue la solution IV de choix pour les
préparations de tels mélanges.
Mots clés : triméthoprime, sulfaméthoxazole, stabilité,
Can J Hosp Pharm 2002;55:207-11 polychlorure de vinyle, verre

C J H P – Vol. 55, No. 3 – June 2002 J C P H – Vol. 55, no 3 – juin 2002 207
INTRODUCTION conducted at room temperature (21°C to 25°C). The
retention times were approximately 5 min for trimethoprim

T rimethoprim–sulfamethoxazole is a clinically useful


drug combination for the prophylaxis and treatment
of serious infections such as Pneumocystis carinii
and approximately 9 min for sulfamethoxazole.
Linearity of the assay was demonstrated for
trimethoprim concentrations ranging from 0.15 to 2.40
pneumonia, an opportunistic infection that occurs mg/mL (r > 0.9999). Standard curves were prepared
in patients with acquired immunodeficiency daily, and the assay was demonstrated to be both
syndrome. Stability guidelines for admixtures containing accurate and reproducible. At a trimethoprim
trimethoprim–sulfamethoxazole range from 2 to 6 h concentration of 1.60 mg/mL, the measured concentration
was within 2% of the expected value; between-day and
depending upon the concentration and the manufacturer.1
within-day variability averaged 3.1% and 2.0%,
This short shelf life creates logistic, administrative, and respectively.
delivery problems for hospital pharmacy and nursing The stability-indicating nature of the assay was
departments and can result in waste of the admixture demonstrated according to the methods described by
and unnecessarily high costs. Kaufman and colleagues.5 Briefly, samples were
The primary factor limiting the shelf life of stressed by addition of hydrochloric acid and hydrogen
admixtures of trimethoprim–sulfamethoxazole is the peroxide with heating at temperatures up to 100°C.
concentration-dependent solubility of trimethoprim, The peak for the stressed trimethoprim sample was
which precipitates over time. Sulfamethoxazole has a smaller than that of the unstressed sample, and
much higher solubility than trimethoprim in the pH additional peaks, which could be differentiated from
range of common IV solutions, and previous studies trimethoprim on the chromatogram, were apparent.
have documented that no significant loss of this drug In addition, admixtures of trimethoprim–
occurs over a 24- to 48-h storage period.2-4 Trimethoprim sulfamethoxazole were allowed to degrade for
is a weak base with reduced solubility at higher pH. 5 months at room temperature, and the resulting
Because the pH of 5% dextrose in water (D5W) is lower samples were compared with a fresh reference
than that of 0.9% sodium chloride (NS), D5W is solution. A distinct degradation product not present
preferred for preparation of trimethoprim– in the reference solution and clearly separated from
sulfamethoxazole admixtures. the trimethoprim peak was observed at 4.32 min
The literature regarding the stability of (Figure 1).
trimethoprim–sulfamethoxazole in various solutions and
containers for IV administration is conflicting.2-7 These
Formulation and Sample Preparation
studies examined storage in syringes, buretrols, and
glass bottles, but there are no published papers Sulfamethoxazole and trimethoprim for injection
examining stability in polyvinylchloride (PVC), concentrate (Elkins-Sinn, Inc., Cherry Hill, New Jersey)
even though PVC bags are widely used for the IV was used. This product contained 16 mg trimethoprim
administration of trimethoprim–sulfamethoxazole. The and 80 mg sulfamethoxazole per milliliter, along with
purpose of this study was to compare the stability of propylene glycol 400 mg, alcohol 10% w/v,
trimethoprim in PVC bags and glass bottles at diethanolamine 3 mg, benzyl alcohol 10 mg, and
concentrations that would be suitable for patients sodium metabisulfite 1 mg in water for injection at a
with fluid restrictions. Stability was assessed in both final pH of 9.5 to 10.5. An appropriate volume of
D5W and NS. concentrate was added to 250-mL evacuated glass
containers and 100-mL PVC bags (Baxter Healthcare
METHODS Corp., Deerfield, Illinois) containing D5W or NS to
produce a final trimethoprim concentration of 1.08
Trimethoprim Analysis and Assay Validation or 1.60 mg/mL. The samples were stored at room
temperature (21°C to 25°C) under ambient light.
Samples were assayed by means of a stability-
indicating high performance liquid chromatography
(HPLC) method based on that described by Kaufman Assessment of Chemical Stability
and colleagues5 and DeAngelis and colleagues.6 The chemical stability of trimethoprim was deter-
A 5-µm C18 reverse-phase analytical column (Partisil
mined by assaying 80 samples of the admixture, 10 for
5 ODS-3, 4.6 mm x 25 cm, Whatman Inc., Clifton, New
Jersey) was used, with a mobile phase consisting of each container type (PVC and glass), IV solution (NS
13% acetonitrile, 1% acetic acid, and 0.1% triethylamine and D5W), and concentration (1.08 and 1.60 mg/mL
(all HPLC grade) pumped at a flow rate of 1.7 mL/min. trimethoprim). Aliquots (0.1 mL each) were removed at
The eluent was monitored with a variable-wavelength 0, 12, and 24 h. Each aliquot was diluted with 0.9 mL
ultraviolet detector set at 254 nm (model 490E, Waters distilled water, and a 100-µL sample was injected into
Associates, Milford, Massachusetts). The analysis was the chromatograph. Standards were also diluted 1:10

208 C J H P – Vol. 55, No. 3 – June 2002 J C P H – Vol. 55, no 3 – juin 2002
with water before injection, and each sample was
assayed in duplicate. Chemical stability was defined as
a decrease in trimethoprim concentration of less than
10% over the 24-h study period. Mean percentage
trimethoprim remaining and 95% confidence limits were
calculated.

Assessment of Physical Stability


Twenty samples of the admixture for each
container type, IV solution, and nominal trimethoprim
concentration were visually inspected at 0, 12, and 24 h
Degradation product 4.32 min for evidence of particulate matter, haze, or colour
change. The pH was measured at 0 and 24 h. To
confirm the results of the visual inspection, selected
samples of the admixture were examined microscopically

Sulfamethoxazole 8.93 min


Sulfamethoxazole 8.81 min

or filtered with a 0.45-µm filter (Pall Gelman Sciences, Ann


Arbor, Michigan). The filters were examined for the
presence of solid material and, when present, the
precipitate was dissolved in mobile phase and injected
into the chromatograph to confirm its identity.

RESULTS
All samples exhibited chemical stability for
trimethoprim (Table 1). The mean trimethoprim
concentration at 24 h was more than 95% of the initial
value, irrespective of container type, IV solution, or
concentration. The lower limit of the 95% confidence
Trimethoprim 5.19 min

interval was greater than 90% in all cases. At 24 h, the


95% confidence interval included the value of 100%
(indicating no degradation) for all samples. Of the 80
Trimethoprim 5.19 min

samples assayed, only 3 exhibited more than a 10% loss


of trimethoprim over 24 hours. These 3 samples were
each stored in glass bottles, and in each case the
decrease in trimethoprim concentration was less than
15%. In all but one of the samples containing a visible
precipitate, trimethoprim concentration remained above
90% of the initial value.
No precipitate was observed in any sample
prepared in a PVC bag at either concentration (Table 2).
For samples stored for 12 h in glass bottles there was no
precipitate in any sample prepared with D5W or in sam-
ples prepared with NS at a nominal concentration of
1.08 mg/mL. However, 4 of 20 samples prepared with
NS at 1.60 mg/mL and stored in glass showed a precip-
Figure 1. Left: Chromatogram of a freshly prepared admixture itate by 12 hours. By 24 hours, a precipitate was
of trimethoprim (retention time 5.19 min) and sulfamethoxazole
(8.81 min). Right: After storage for 5 months at room
observed in numerous of the samples prepared and
temperature, a degradation product with a retention time of stored in glass (Table 2). Precipitation was most
4.32 min became apparent. frequent in NS at the higher concentration of trimethoprim
(1.60 mg/mL). The retention time of material recovered
from the filter paper, redissolved in mobile phase, and
injected into the chromatograph matched that of
trimethoprim. No crystals were detected under the
microscope or on the filter paper in any admixture that
was visually free of precipitate.

C J H P – Vol. 55, No. 3 – June 2002 J C P H – Vol. 55, no 3 – juin 2002 209
Table 1. Chemical Stability of Trimethoprim in Admixtures with Sulfamethoxazole Stored at Room
Temperature over 24 h

Mean Concentration Mean % Trimethoprim


and SD (mg/mL) Remaining and 95% CI
Solvent and Storage Container Nominal Actual Initial At 12 h At 24 h
D5W
PVC 1.08 1.00 (0.05) 99.2 (97.3–101.01) 98.7 (95.8–101.6)
1.60 1.39 (0.06) 101.2 (98.0–104.4) 101.0 (97.6–04.4)
Glass 1.08 1.05 (0.03) 99.7 (97.1–102.3) 98.5 (94.6–102.4)
1.60 1.62 (0.04) 97.8 (94.3–101.3) 100.7 (98.6–102.8)
NS
PVC 1.08 1.03 (0.03) 99.2 (97.7–100.7) 100.0 (98.4–101.6)
1.60 1.36 (0.05) 99.4 (96.1–102.7) 98.3 (94.6–102.0)
Glass 1.08 1.07 (0.03) 97.0 (95.4–98.6) 96.0 (91.9–100.1)
1.60 1.58 (0.04) 99.2 (96.5–101.9) 99.9 (97.4–102.4)
SD = standard deviation, CI = confidence interval, D5W = 5% dextrose in water, PVC = polyvinylchloride, NS = normal saline.

Table 2. Presence of Precipitate* in Admixtures of 2 h in D5W at a concentration of 1.6 mg/mL in buretrols


Trimethoprim–Sulfamethoxazole at 24 h made of cellulose proprionate. The relevance of these
data to current practice is limited, because buretrols
Nominal are not commonly used for administration of
Concentration of
trimethoprim–sulfamethoxazole. Two studies have
Trimethoprim Glass PVC Bags
(mg/mL) NS D5W NS D5W examined the stability of this admixture in glass
1.08 2/20 4/20 0/20 0/20 containers. Deans and colleagues3 reported that the
1.60 14/20 5/20 0/20 0/20 solution was stable for up to 24 h in both D5W and NS
PVC = polyvinylchloride, NS = normal saline, D5W = 5% dextrose in water.
at concentrations ranging from 0.64 to 1.6 mg/mL
*Visible to unaided eye. Data presented as number of samples showing trimethoprim. In contrast, Jarosinski and colleagues4
precipitate/total number of samples. found that the stability in glass was markedly dependent
on concentration. For trimethoprim 0.8 mg/mL in D5W,
the admixture was stable for 24 h. However, the period
The actual concentration of trimethoprim in PVC of stability was reduced to 4 h at 1.07 mg/mL and to
bags was consistently 5% to 10% below that in glass 1 h at 1.6 mg/mL. In addition, both Lesko and
(Table 1). To ensure that lower concentrations were not colleagues2 and Jarosinski and colleagues4 concluded
a confounding factor in the superior performance of the that solubility was higher in D5W than NS. Admixtures
bags, 10 admixtures were prepared at a trimethoprim prepared in D5W have a lower pH than those prepared
concentration of 2.00 mg/mL in D5W and stored in PVC in NS (8.94 and 9.81, respectively, in this study), which
bags. A precipitate was observed in only 1 of the 10 would favour the aqueous solubility of a weak base
samples at 24 h. such as trimethoprim. Although the results of these
No changes in pH occurred over the 24-h observa- studies differ significantly, current recommendations
tion period. In addition, there were no differences in the favour the more conservative stability times suggested
pH of admixtures prepared and stored in glass and PVC. by Jarosinski and colleagues.4 However, neither of these
As expected, the pH of the NS samples was higher than studies2,4 examined stability in PVC minibags, the most
that of the D5W samples (9.81 and 8.94, respectively). common container in current clinical use for admixtures
The pH of samples containing 1.60 mg/mL trimethoprim of trimethoprim–sulfamethoxazole.
was approximately 0.1 to 0.2 higher than that of samples The results of the current study suggest that the
containing 1.08 mg/mL trimethoprim. chemical stability of trimethoprim is maintained for 24 h
in both glass and PVC (Table 1). The HPLC assay
separated trimethoprim from sulfamethoxazole in the
DISCUSSION
admixture (no other peaks were observed) and was
Several studies have examined the stability of capable of indicating stability, as evidenced by the
trimethoprim–sulfamethoxazole over the past 20 years, appearance of new peaks that could be readily
with conflicting results. Lesko and colleagues2 found distinguished from trimethoprim in a sample acutely
that the trimethoprim component was stable for only stressed or degraded for 5 months at room temperature

210 C J H P – Vol. 55, No. 3 – June 2002 J C P H – Vol. 55, no 3 – juin 2002
(Figure 1). This result is not particularly surprising, since The results of this study indicate that trimethoprim
it is physical stability rather than chemical stability that in admixtures with sulfamethoxazole is physically stable
is the primary factor affecting the shelf life of this for a longer period in PVC minibags than in glass
product. It is interesting that several samples with a bottles. Admixtures prepared in PVC minibags at
precipitate visible to the naked eye maintained a concentrations up to 1.60 mg/mL can be stored for up
trimethoprim concentration greater than 90% of the to 24 h at room temperature. Although D5W is the
initial value. Admixtures at a concentration of recommended IV solution, NS can be used for patients
1.60 mg/mL in 250-mL glass bottles contain 400 mg in whom use of D5W is not desirable; stability will not
trimethoprim. Precipitation of 5% of the trimethoprim, be significantly compromised if such admixtures are
for example, would represent 20 mg of compound, a prepared in PVC containers. If glass bottles are used,
quantity that can easily be detected by visual inspection trimethoprim–sulfamethoxazole should be prepared in
of the IV container. D5W and stored for no longer than 12 h.
Although chemical stability was acceptable in both
types of container, there were significant differences in References
physical stability between glass and PVC containers. No 1. Sulfamethoxazole and trimethoprim, concentrate for injection
precipitate was observed in any admixture prepared in package insert. Cherry Hill (NJ): Elkin-Sinn Inc; 1990.
PVC minibags at either nominal concentration. To 2. Lesko LJ, Marion A, Ericson J, Siber GR. Stability of trimethoprim–
confirm that the visual inspection was accurate, selected sulfamethoxazole injection in two infusion fluids. Am J Hosp
samples were subjected to microscopic examination. No Pharm 1981;38:1004-6.
evidence of crystal formation could be detected under 3. Deans KW, Lang JR, Smith DE. Stability of trimethoprim–
sulfamethoxazole injection in five infusion fluids. Am J Hosp
the microscope. In addition, admixtures that appeared Pharm 1982;39:1681-4.
to be free of precipitate were filtered, and the filter
4. Jarosinski PF, Kennedy PE, Gallelli JF. Stability of concentrated
paper was examined for evidence of particulate matter. trimethoprim–sulfamethoxazole admixtures. Am J Hosp Pharm
No precipitated material was recovered from the filter 1989;46:732-7.
paper in any such case. When samples with precipitate 5. Kaufman MB, Scavone JM, Foley JJ. Stability of undiluted trimethoprim–
visible to the naked eye were filtered, the precipitate sulfamethoxazole for injection in plastic syringes. Am J Hosp
was recovered and identified by HPLC as trimethoprim. Pharm 1992;49:2782-3.
The physical stability of trimethoprim in glass 6. DeAngelis DV, Woolley JL, Sigel CW. High-performance liquid
containers was much less than that in PVC minibags, chromatographic assay for the simultaneous measurement of
trimethoprim and sulfamethoxazole in plasma and urine. Ther
with stability times longer than reported by Jarosinski Drug Monit 1990;12:382-92.
and colleagues4 but shorter than those suggested 7. McDonald C, Faridah J. Solubilities of trimethoprim and
by Deans and colleagues.3 Significant evidence of sulfamethoxazole at various pH values and crystallization of
precipitation was present at 24 h, particularly in NS and trimethoprim from infusion fluids. J Parenter Sci Technol
at the higher concentration of trimethoprim (Table 2). 1991;45:147-51.
However, no physical instability was observed in the
D5W samples at 12 h, which suggests that even in glass,
James M. Curtis, PharmD, is Clinical Pharmacy Specialist, Pharmacy
admixtures prepared in D5W can be safely stored for Department, Borgess Medical Center, Kalamazoo, Michigan.
up to 12 h.
David J. Edwards, PharmD, is Professor, Department of Pharmacy
The concentrations of trimethoprim in samples Practice, College of Pharmacy and Allied Health Professions, Wayne
prepared in PVC bags were 5% to 10% lower than those State University, Detroit, Michigan.
observed in glass bottles. Whether this difference was
Address correspondence to:
related to the overfill volume of PVC bags, adsorption of Dr David J. Edwards
drug to the bag, or some other aspect of the preparation Department of Pharmacy Practice
of the admixtures requires further investigation and Eugene Applebaum College of Pharmacy and Health Sciences
confirmation. However, the slightly lower concentration Wayne State University
of trimethoprim in minibags at a nominal concentration Detroit MI
48202
of 1.60 mg/mL could in theory contribute to the less
e-mail: dje@wizard.pharm.wayne.edu
frequent occurrence of precipitation in these samples
than in glass. To rule out this possibility, 10 admixtures Acknowledgements
were prepared in PVC bags at a trimethoprim This study was supported by an Undergraduate Research Award from
Wayne State University. Portions of this work were presented at the
concentration above that normally used in clinical
American Society of Health-System Pharmacists (ASHP) Mid-Year
practice (2.00 mg/mL). The frequency of precipitation Clinical Meeting, December 1998, Las Vegas, Nevada, where
(1/10) was much lower than observed with glass bottles Dr Curtis received the Student Research Award of the ASHP Research
at either 1.08 or 1.60 mg/mL (Table 2). and Education Foundation.

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